ABSTRACT The purpose of this article is to review progress in the field of abdominopelvic adhesions and the validity of its two underlying assumptions: (1) The formation of adhesions results in infertility, bowel obstruction, or other complications. Reducing or avoiding adhesions will curb these sequelae. (2) "Adhesions" is a monolithic entity to be tackled without regard to any other condition. Evidence is discussed to validate the first assumption. We reviewed progress in the field by examining hospital data. We found a growing trend in the number and cost of discharges for just two adhesion-related diagnoses, and the low usage of adhesion barriers appears in at most 5% of appropriate procedures. Data from an Internet-based survey suggested that the problem may be partly due to ignorance among patients and physicians about adhesions and their prevention. Two other surveys of patients visiting the adhesions.org Web site defined more fully adhesion-related disorder (ARD). The first survey ( N = 466) described a patient with chronic pain, gastrointestinal disturbances, an average of nine bowel obstructions, and an inability to work or maintain family or social relationships. The second survey (687 U.S. women) found a high (co-) prevalence of abdominal or pelvic adhesions (85%), chronic abdominal or pelvic pain (69%), irritable bowel syndrome (55%), recurrent bowel obstruction (44%), endometriosis (40%), and interstitial cystitis (29%). This pattern suggests that although "adhesions" may start out as a monolithic entity, an adhesions patient may develop related conditions (ARD) until they merge into an independent entity where they are practically indistinguishable from patients with multiple symptoms originating from other abdominopelvic conditions such as pelvic or bladder pain. Rather than use terms that constrain the required multidisciplinary, biopsychosocial approach to these patients by the paradigms of the specialty related to the patient's initial symptom set, the term complex abdominopelvic and pain syndrome (CAPPS) is proposed. It is essential to understand not only the pathogenesis of the "initiating" conditions but also how they progress to CAPPS. In our ARD sample, not only was the frequency of women with hysterectomies (56%) higher than expected (21 to 33%), but also the rates of the "initiating" conditions was 40 to 400% higher in patients with hysterectomies than in those without. This may represent increased surgical trauma or the loss of protection against oxidative stress. Related was the higher frequency of ARD patients reporting hemochromatosis (HC; 5%) than expected (~0.5%) and the higher rates (20 to 700%) of initiating conditions in patients with HC than in those without HC. Together with findings related to the toxicity of Intergel, these findings raise the possibility that heterozygotes for genes regulating oxidative stress are at greater risk of developing surgical complications as well as more severe and progressive conditions such as CAPPS.

[Show abstract][Hide abstract]ABSTRACT:
BackgroundPelvic adhesions are found in up to 50% of women with CPP during investigative surgeries and adhesiolysis is often performed as part of their management although the causal or casual association of adhesions, and the clinical benefit of adhesiolysis in the context of CPP is still unclear. Our aim was to test the hypothesis of whether laparoscopic adhesiolysis leads to significant pain relief and improvement in quality of life (QoL) in patients with chronic pelvic pain (CPP) and adhesions.MethodsThis was a double-blinded RCT. This study was conducted in 2 tertiary referral hospitals in United Kingdom over 4 years. Women with chronic pelvic pain (CPP) were randomized into having laparoscopic adhesiolysis or diagnostic laparoscopy. Women were assessed at 0, 3 and 6 months for Visual analogue scale scores (VAS) and Quality of Life (QoL) measures (SF-12 and EHP-30).ResultsA total of 92 participants were recruited; 50 qualified to be randomized, with 26 in the adhesiolysis and 24 in the control group. The results are expressed in median (interquartile ranges). In women who underwent adhesiolysis, there was a significant improvement at 6 months in VAS scores (-17.5 (-36.0 - -5.0) compared to controls (-1.5 (-15.0 – 4.5; p = 0.048); SF-12 scores physical component score (25.0 (18.8 – 43.8)) compared to controls (6.3 (-6.3 – 18.8); p = 0.021), SF-12 emotional component score 32.5 (4.4 – 48.8) compared to controls -5 (-21.3 – 15.0); p < 0.0074) and EHP-30 emotional well being domain 32.5 (4.4 – 48.8) compared to the controls -5 (-21.3 – 15.0; p < 0.0074).ConclusionsThis study stopped before recruitment reached the statistically powered sample size due to difficulty with enrollment and lack of continued funding. In selected population of women presenting to the gynecological clinic with chronic pelvic pain, adhesiolysis in those who have adhesions may be of benefit in terms of improvement of pain and their quality of life.Trial registration numberISRCTN 43852269

[Show abstract][Hide abstract]ABSTRACT:
Intra-abdominal adhesions are a common source of postoperative morbidity. Previous studies in our laboratory have shown that a neurokinin 1 receptor antagonist (NK-1RA) reduces abdominal adhesion formation and increases peritoneal fibrinolytic activity. However, the cellular pathway by which the antagonist exerts its effects is unclear, as cultured peritoneal mesothelial cells exposed to the NK-1RA show increases in fibrinolytic activity despite having very low expression of neurokinin 1 receptor (NK-1R) messenger RNA and protein. Our aim was to determine whether the NK-1R plays an essential role in the adhesion-reducing effects of the NK-1RA, or if the NK-1RA is acting independently of the receptor.

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Disorders of Adhesions or Adhesion-RelatedDisorder: Monolithic Entities or Partof Something Bigger—CAPPS?David M. Wiseman, Ph.D., M.R.Pharm.S.1ABSTRACTThe purpose of this article is to review progress in the field of abdominopelvicadhesions and the validity of its two underlying assumptions: (1) The formation ofadhesions results in infertility, bowel obstruction, or other complications. Reducing oravoiding adhesions will curb these sequelae. (2) ‘‘Adhesions’’ is a monolithic entity to betackled without regard to any other condition.Evidence is discussed to validate the first assumption. We reviewed progress in thefield by examining hospital data. We found a growing trend in the number and cost ofdischarges for just two adhesion-related diagnoses, and the low usage of adhesion barriersappears in at most 5% of appropriate procedures. Data from an Internet-based surveysuggested that the problem may be partly due to ignorance among patients and physiciansabout adhesions and their prevention.Two other surveys of patients visiting the adhesions.org Web site defined morefully adhesion-related disorder (ARD). The first survey (N¼466) described a patient withchronic pain, gastrointestinal disturbances, an average of nine bowel obstructions, and aninability to work or maintain family or social relationships. The second survey (687 U.S.women) found a high (co-) prevalence of abdominal or pelvic adhesions (85%), chronicabdominal or pelvic pain (69%), irritable bowel syndrome (55%), recurrent bowelobstruction (44%), endometriosis (40%), and interstitial cystitis (29%).This pattern suggests that although ‘‘adhesions’’ may start out as a monolithicentity, an adhesions patient may develop related conditions (ARD) until they merge into anindependent entity where they are practically indistinguishable from patients with multiplesymptoms originating from other abdominopelvic conditions such as pelvic or bladder pain.Rather than use terms that constrain the required multidisciplinary, biopsychosocialapproach to these patients by the paradigms of the specialty related to the patient’s initialsymptom set, the term complex abdominopelvic and pain syndrome (CAPPS) is proposed.It is essential to understand not only the pathogenesis of the ‘‘initiating’’conditions but also how they progress to CAPPS. In our ARD sample, not only was thefrequency of women with hysterectomies (56%) higher than expected (21 to 33%), but alsothe rates of the ‘‘initiating’’ conditions was 40 to 400% higher in patients with hysterec-tomies than in those without. This may represent increased surgical trauma or the loss ofprotection against oxidative stress. Related was the higher frequency of ARD patientsreporting hemochromatosis (HC; 5%) than expected (?0.5%) and the higher rates (20 to1Synechion, Inc., and International Adhesions Society, Dallas, Texas.Address for correspondence and reprint requests: David M.Wiseman, Ph.D., PMB 238, International Adhesions Society, 6757Arapaho, Suite 711-238, Dallas, TX 75248 (e-mail: david.wiseman@adhesions.org).Postsurgical Adhesions; Guest Editor, Michael P. Diamond, M.D.Semin Reprod Med 2008;26:356–368. Copyright # 2008 byThieme Medical Publishers, Inc., 333 Seventh Avenue, New York,NY 10001, USA. Tel: +1(212) 584-4662.DOI 10.1055/s-0028-1082394. ISSN 1526-8004.356

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700%) of initiating conditions in patients with HC than in those without HC. Togetherwith findings related to the toxicity of Intergel, these findings raise the possibility thatheterozygotes for genes regulating oxidative stress are at greater risk of developing surgicalcomplications as well as more severe and progressive conditions such as CAPPS.KEYWORDS: Adhesions, adhesion-related disorder, complex abdominopelvic and painsyndrome, chronic pelvic pain, hysterectomy, iron overload, hemochromatosisThe history of adhesion prevention has beenanalyzed in terms of six epochs1divided principallyaccording to the level of sophistication of the approachesused. The period referred to as ‘‘The Industrial Revolu-tion’’ starting around 1989 was marked by the introduc-tion of Interceed (1989; Ethicon, Inc, Somerville, NJ),2Seprafilm (1996; Genzyme Corp; Cambridge, MA),3,4Preclude (ca. 1990; WL Gore & Associates, Flagstaff,AZ)5and Adept (2007; Baxter Healthcare Corporation,Deerfield, IL). Hyaluronic acid, Flogel (poloxamer; Alli-ance Pharmaceutical Corp., San Diego, CA), tolmetin,Focalgel (Focal, Inc., Lexington, MA), and tissue-typeplasminogen activator were all evaluated for adhesionprevention, but did not reach the point of regulatorysubmission. Sepracoat (1997; Genzyme Corp, Cam-bridge, MA)6was denied approval, and Intergel (2002;Ethicon, Inc., Somerville, NJ)7was approved but with-drawnforsafetyreasons.8Adcon-L (1998; Gliatech,Inc.,Cleveland, OH) was approved for spinal surgery but laterwithdrawn. Seprafilm II was briefly available in Europebut discontinued, and SprayGel (Covidien, Mansfield,MA), and Hylagel (Fidia Advanced Biopolymers, s.r.l.Abano Terme, Italy) remain available only outside theUnited States.This ‘‘Industrial Revolution’’ has fueled an explo-sion in our grasp of abdominopelvic adhesions andits etiology,9–11epidemiology,12,13cost,14–16preventionin human17and animal18models, as well as its clinicalmanifestations of pain, infertility, and bowel obstruc-tion.10,19–21Two assumptions underlying the contem-porary study of adhesions and their prevention are thefollowing:1. The formation of adhesions results in infertility,bowel obstruction, or other complications. Reducingor avoiding adhesions will curb these sequelae.2. ‘‘Adhesions’’ is a monolithic entity to be tackledwithout regard to any other condition.The purpose of this article is to review ourprogress in the field and its underlying assumptions.DOES REMOVAL OR AVOIDANCEOF ADHESIONS IMPROVE PATIENTOUTCOMES?It has long been argued that the collection of outcome-based data for regulatory purposes would be impracticaldue to the multifactorial nature of pain and infertility orthe prolonged follow-up required in large numbers ofpatients to evaluate bowel obstruction.22Nonetheless,studies have emerged that permit us to test our hypoth-eses that the removal (i.e., adhesiolysis) or avoidance ofadhesions (i.e., use of adhesion barriers) will result inclinical benefits.Adhesion Reduction and SurgicalComplicationsThat the reduction in adhesion formation would resultin the overall reduction of surgical complications isobvious from the several epidemiologic studies findingthat approximately one third of patients undergoingabdominal or pelvic surgery were admitted nearlytwice in the next 10 years for a problem related toadhesions or that could be complicated by adhe-sions.13,23The same argument is justified from thenumerous studies showing the reduction in incidence,extent, or severity of adhesions using a variety ofadhesion barriers. More direct evidence comes froma small retrospective study involving 52 patientsundergoing a second cesarean section, which foundthat delivery times and operative times were reducedin patients having Seprafilm placed at a first cesareansection compared with those in patients where Sepra-film was not used. Blood loss was also reduced but didnot reach significance.24Relaparotomy time was alsoreduced in children treated with Seprafilm (N¼67)undergoing abdominal surgery compared with that ofcontrol patients.25A prospective randomized studyfailed in 191 patients to demonstrate any significantdifferences in the time to close a loop ileostomy ifSeprafilm had been used at the time of ileostomycreation. This failure was attributed to the variabilityin techniques used by the large number of surgeons(29) participating in the study.26Adhesion Reduction and InfertilityThe American Fertility Society (AFS) classification ofadnexal adhesions27inherently acknowledges an inverserelationship between adhesions and fertility28andhas been confirmed in two ways. First, pregnancy rateshave correlated with AFS scores (before adhesiolysis)in prospective settings by both laparotomy29and laparo-scopy.30Second, the pregnancy rates among infertileDISORDERS OF ADHESIONS OR ARD/WISEMAN357

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women treated by salpingo-ovariolysis was higher (45%)than that among matched untreated patients (16%).31Although the hypothesis that fertility can be improvedusing an adhesion barrier remains untested prospectively,78% (18 of 23) of patients undergoing reconstructivepelvic surgery treated with Interceed barrier becamepregnant compared with only 47% (7 of 15) of controlpatients.32Adhesion Reduction and Bowel ObstructionThe relationship between bowel obstruction and adhe-sions is well-known19,21,33of bowel obstruction well described.19,34,35Recently,Seprafilm was shown to reduce the rate of adhesivesmall bowel obstruction (SBO) requiring operationfrom 3.4% to 1.8% in 1701 patients undergoing smallbowel resection with a follow-up of 2 to 5 years.36Intwo smaller retrospective series, Seprafilm reduced earlySBO after surgery from 14% (26 of 183) to 6.5% (12 of184) in patients undergoing gastrointestinal surgery37and from 20% (6 of 30) to 0% (0 of 21) in patientsundergoing surgery for transabdominal aortic aneur-ysm.38A meta-analysis failed to detect a benefitof Seprafilm in terms of postoperative intestinalobstruction.39and the managementAdhesion Reduction and PainThe relationship between adhesions and chronic ab-dominal or pelvic pain is more controversial.21,40,41Adhesions may cause pelvic pain by tethering tissues,causing nerve traction, or by entrapping nerves. Indeed,nerve endings have been found within adhesions.42Not all adhesions cause pain, and not all pain iscaused by adhesions. Part of the problem appears to be inthe complex way pain is referred within the abdominalcavity as evidenced from studies involving conscious painmapping. Furthermore, the conventional view that densevascular adhesions are ‘‘worse’’ than filmy adhesions ischallenged by observations that higher pain scores areassociated more with filmy adhesions between movablestructures rather than fixed or dense adhesions.43Twenty-five percent to 57% of patients with chronicpelvic pain (CPP) are estimated to have adhesions, withor without endometriosis.44In 75% of patients with aphysical source of pain, emotional factors contributegreatly to the perception of pain and the ability to copewith it.Despite the uncertain relationship between adhe-sions and pain, adhesiolysis does provide some relief. Ina German study45involving laparoscopic adhesiolysisin female and male patients with chronic abdominalpain, there was a complete remission of pain in 45%of the patients, with 35% of patients reporting a sub-stantial improvement up to 30 months. Other improve-ments were reported in the United States46,47and TheNetherlands.48That these effects may be rooted in a‘‘therapeutic’’ effect of laparoscopy itself alone is notclear as patients without obvious pathology undergoingdiagnostic laparoscopy also reported a reduction orcessation of pain.49To test this further, 100 patients undergoingdiagnostic laparoscopy for chronic abdominal painwere randomized to adhesiolysis or no treatment.50Patients and assessors were blinded. Forty-two percentof patients undergoing diagnostic laparoscopy reportedimprovement or remission at 12 months compared with57% with adhesiolysis. The authors’ conclusion thatalthough laparoscopic adhesiolysis relieved pain, it wasno better than diagnostic laparoscopy, may reflect a typeII error. Further, the apparent benefit of laparoscopyalone suggests that the source of pain in these patientsmay originate less from pathologic (i.e., adhesions) fociin the abdomen and more from higher levels in thenervous system. Whether this ‘‘placebo’’ effect is relatedto that reported in arthroscopy51is unclear, although amore recent prospective and randomized study in endo-metriosis patients undergoing laparoscopy also suggestsa positive effect of ‘‘sham’’ surgery.52Lastly, the likelyreformation of adhesions in at least 75% of surgicalsites53may have abrogated any positive effect of adhe-siolysis. In fact, the difference in pain reduction betweenthe adhesiolysis and control groups would be consistentwith the expected degree of improvement from adhe-siolysis. Perhaps with a reduction of 25 to 30% in theincidence of adhesions (by site) that could be achievedwith adhesion barriers, an effect of adhesiolysis on painmay have been more apparent. Indeed, in an uncon-trolled series of 19 patients undergoing laparoscopicadhesiolysis with placement of Seprafilm for chronicintractable abdominal pain, 14 (74%) patients had dis-continued pain medications at follow-up of up to32 months.54REMOVAL OR AVOIDANCE OF ADHESIONSMAY IMPROVE PATIENT OUTCOMES—NOW WHAT?The emerging evidence does support the notion thatcurbing adhesions improves outcomes for patients. But itis clear that there is a long way to go to eliminate theproblems of adhesionsOur own analysis of discharge data from theNationwide Inpatient Sample for the period 2001–2005 reveals a growing trend in the numbers of dis-charges for just two ICD-9-CM diagnosis codes(Table 1). A somewhat steady 2100 to 2400 patients ayear have died with a principal diagnosis of IntestinalAdhesions with Obstruction (560.81), which producedin 2005 73,881 discharges and some $3.45 billion ofcharges. But this is just the tip of the iceberg. When358SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 26, NUMBER 42008

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other inpatient diagnoses of peritoneal and pelvic adhe-sions are added, the financial cost of adhesions easilyexceeds $5 billion, and that is before outpatient costs andloss of work are considered.The use of adhesion barriers as evidenced fromcode 99.77 is also very low. This is almost certainly anunderestimate. Based on estimated sales of adhesionbarriers of $100 million, an average price per unit of$200, and an average usage of 1 unit per procedure,adhesion barriers are only used, conservatively, in500,000 procedures annually. To estimate their potentialusage, assuming that obstruction due to adhesions rep-resents 1% of general surgical admissions in 1 year,55then the figure of 99,075 discharges for intestinal adhe-sions with obstruction represents some 9.9 million pro-cedures where barriers might be used. The percentage ofprocedures in which adhesion barriers are used is at besta little over 5%.Solving the problem of adhesions may be brokendown into four main tasks:1. Develop more effective antiadhesion agents for avariety of indications both by laparotomy and laparo-scopy.2. Expand basic research beyond that currently con-ducted by a handful of laboratories.3. Increase physician and patient awareness aboutadhesions and their prevention to improve the useof adhesion barriers and other techniques, leading tomore chances for improved outcomes.4. Challenge the paradigms on which are based con-temporary efforts in adhesion prevention. Is it timefor a different look?The development of more advanced antiadhesionagents has been discussed elsewhere,1,56and other con-tributions in this issue of Seminars in ReproductiveMedicine provide a glimpse of the excellent basic researchbeing conducted in the field. The last two items will bediscussed further here.IMPROVING PHYSICIAN AND PATIENTAWARENESS ABOUT ADHESIONSThe ramifications of physician and patient ignoranceabout adhesions has long been the subject of debate inthe boardrooms of medical product companies and thebarrooms of conferences on adhesions. Corporate adver-tising as well as sponsorship of several excellent studiessuch as those analyzing data from the Scottish NationalHealth Service12,13has greatly increased awareness ofadhesions. Revolutionizing patients’ access and use ofmedical information, the Internet has spawned theproliferation of Web sites promoting research andawareness and providing information and supportto families and patients affected with all manner ofconditions, particularly those heretofore relegated toobscurity in medical textbooks. Accordingly, in 1996we formed The International Adhesions Society, and itsadhesions.org Web site now receives more than 100,000visitors monthly. Ignorance about adhesions amongpatients and physicians is frequently reported to us,arguably delaying diagnosis and treatment and inflictingadditional suffering on patients shunned by their physi-cians, employers, and families as malingerers.To characterize the causes of this ignorance,patients who had abdominal or pelvic surgeries weresurveyed via the Internet57about information giventhem prior to surgery regarding adhesions and adhesionbarriers. Five hundred seventy (43 male, 527 female)patients responded concerning 952 procedures. Patientsreported being informed about adhesions prior to 27% ofthe procedures they underwent. In only 122 (12.8%) ofthese were adhesions mentioned as part of the informedTable 1Hospital Discharge Data for Two Adhesion-Related Codes and Use of BarriersYear2001 2002200320042005ICD-9-CM Diagnosis Code 568.0 Peritoneal AdhesionsAll Diagnoses—DischargesAll discharges 156,621168,154172,935180,806186,387Female percent of total (%)ICD-9-CM Diagnosis Code 560.81, Intestinal Adhesions with Obstruction747372 7372All Diagnoses—DischargesAll discharges89,04891,66488,96594,708 99,075Female percent of total (%)6362626262Principal Diagnosis Only—DeathsAll22192366231121402118Female13961404141812641285Female deaths as percent of female discharges (%)99.77 Application of Adhesion Barrier3.253.193.362.812.78——23,81330,105Source: Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality.DISORDERS OF ADHESIONS OR ARD/WISEMAN359

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consent, and in another 132 (13.9%) adhesions werediscussed. Information was imparted about adhesions in55% of adhesiolysis procedures and in 9.3% of non–adhesiolysis procedures. Patients reported being providedwith information about adhesion barriers in 46% and 6%of adhesiolysis and non–adhesiolysis procedures, respec-tively. Where adhesions were mentioned, barriers werementioned in 46% of adhesiolysis procedures and in 22%of non–adhesiolysis procedures. Despite several obviouscaveats involved in interpreting a study of this kind,it suggests the preoperative consultation and consentprocedures may offer the ideal opportunity to educatepatients about adhesions. Beyond medicolegal reasons fordiscussing adhesions,58patients do want to know abouttheir treatment and its risks.59Even if they do not fullyunderstand the information provided,60training (or evenrequiring) physicians to discuss adhesions with patientsforces them to consider a strategy for their reduction.CHALLENGING THE PARADIGMSOF ADHESIONS RESEARCH: IS IT TIMEFOR A DIFFERENT LOOK?Viewing the Problem as Adhesion-RelatedDisorderDespite the increasing volume of work conducted, ad-hesions research has been practically compartmentalized,as if ‘‘adhesions’’ was an independent entity. Accord-ingly, the approach to ‘‘adhesions’’ patients was muchlike any monolithic disease but was clearly not meetingthe needs of thousands of ‘‘adhesions’’ patients seekingreferrals or other information. Why? Because we lackedeffective antiadhesion agents? Because we did not fullyunderstand the pathogenesis of adhesions? Because ofignorance about adhesions and their prevention? Per-haps it was because we wrongly assumed that ‘‘adhe-sions’’ is an independent and monolithic problem.To determine the best approach to the ‘‘adhe-sions’’ patient, we first tried to describe more fully thecondition of the ‘‘adhesions’’ patient. From hundreds ofe-mails and telephone interviews, a typical picture of an‘‘adhesions’’ patient emerged of a 30- to 50-year-oldwoman with several abdominal surgeries, including ahysterectomy and several bowel obstructions. She hadchronic pain, could not eat properly, and had alreadyseen several physicians who had told her that there waslittle to be done. The patient was desperate and frus-trated and her family, social, and employment relation-ships were deteriorating.An Internet-based survey was conducted to quan-tify what we had learned from our anecdotal library.61Four hundred sixty-six patients (51 male, 415 female)reported having a diagnosis of adhesions for 7.0?0.3 years. Sixty-eight percent of patients reported anaverage of 9.5?0.7 full or partial obstructions. Most ofthese respondents seem to represent a severe form of‘‘adhesions’’ perhaps a notch or two below the 2100 or sopatients dying annually with a primary diagnosis ofintestinal adhesions with obstruction (Table 1). Thesedata are consistent with descriptions of a living hell inwhich each of the sometimes >25 adhesiolysis proce-dures offers only a temporary respite of less than a yearfrom obstruction and debilitating pain. Indeed, 81% ofrespondents reported chronic pain of whom 68% tookmedication. In 68% of those patients, the medicationworsened their bowel symptoms. Seventy-one percent ofpatients reported gastrointestinal disturbances, including52% with chronic or severe constipation, 30% withchronic or severe diarrhea, and 24% with malabsorptionproblems. The totality of these patients’ suffering couldnot adequately be described by the monolithic term‘‘adhesions’’ and so was coined the term adhesion-relateddisorder (ARD).Our anecdotal impression that ARD compro-mises a patient’s ability to work was verified by 42% ofrespondents, 47% of whom could not obtain disabilitybenefits. As a result of their condition, patients reportedthat either their relationships had suffered (57%) or theirfriends and family were not supportive (44%), or both(27%), with only 26% reporting intact relationships andsupportive friends and family.Commonly reported feelings of isolation and‘‘craziness’’ are illustrated in the following excerptsfrom e-mails we received (without correction of spellingor grammar):? have had 15 srgys. Each time the doctors go in theysay I had so much ashesions. I had a hsty 4 years agobecause of endo. Now the pain is back in full force. Atfirst I thought I was crazy... I do not no how long Ican deal with this pain. Its so bad. Is there anyone whohas gone though this before. I could really use someencouragement right now. I thought the pain wasgone after the hsty. I guess I was wrong (9/9/2002).? I have been suffering with endometriosis, adhesions,and IC [interstitial cystitis] for the past 13 years. Ihave had 24 surgeries and still live in constant painfrom adhesions.... Without pain meds I cannot takecare of my children or my husband. I cannot workanymore.... The adhesion site has been a savior to meat a time in my life when I thought I was all alone.Now I know I am not alone and there are otheralternatives to just living in pain the rest of my life(5/10/2004).? I thought I was the only one. I have had 12 surgeries tocontrol the adhesions.... I thought I was going to beatthis one, but now the symptoms have returned and allmy hope has gone.... Thanks for posting this Websitewhere I can know i’m not the only one.(4/17/2006).In the extreme, some patients reported consider-ing or attempting suicide:360SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 26, NUMBER 42008

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? i really don’t know what to do anymore... ii am toscared to ask for help but i really want it... I am soready to just commit suicide but i never succeed (10/9/2003).? I.... feel suicidal trying to cope with ARD (3/6/2006).? I lost another ARD patient this past weekend tosuicide. Her family and friends were no support forher. He[r husband] was told her only problem wasaddiction to pain meds. That was the last straw,...(from an ARD volunteer 10/2/2006).? I had a full hysterectomy... I am in constant pelvic/abdominal pain.... had.... additional surgeries foradhesions.... I am still in constant pain 24–7.... I amso depressed with thoughts of suicide, however, mydeep faith will always prevent me from doing this (12/24/2004).Based on anecdotal reports, patients were alsoasked about their use of physical therapy. In the 26% ofpatients using it, 29% benefited. Such therapy has beenwidely reported to benefit patients with a diagnosis ofchronic pelvic pain.62Forty percent of patients reportedthat their physician was able to help their conditionsomewhat, with another 51% reporting that their physi-cians acknowledged their problem but were unable tohelp. Contrary to earlier impressions, only 9% of patientsreported that their physicians denied their problem andwere unwilling to help.Viewing ARD in the Context of ComplexAbdominopelvic and Pain Syndrome (CAPPS)The term ARD still leaves the same frustrated anddesperate patient traversing continents and oceans inthe hope of finding that one physician with ‘‘the secret’’to their suffering. Continuing to puzzle us are obser-vations that severe ARD patients are temporarily re-lieved of pain after adhesiolysis, and when pain recursthey are adhesion-free (and free of other pathology) atlaparoscopy. Equally puzzling is the improvement inpain after diagnostic laparoscopy alone in patients withadhesions.50If by using the term ARD we have suc-ceeded in acknowledging the existence of ARD pa-tients’ numerous symptoms, we continue to failpractically by assuming that they are all related by thecommon denominator of adhesions. As will be ex-plained, a more successful approach may be derivedby examining the problem of ARD in the context of amuch larger problem of what we have termed complexabdominopelvic and pain syndrome (CAPPS) definedoperationally as:a syndrome of nonmalignant origin consisting ofa complex of symptoms of the abdomen or pelvis thatincludes pain, bowel, or bladder dysfunction of at least6 months duration.Both sides of the debate about whether adhesionscause pain have failed to consider neurologic changesthat occur in chronic pain. Although acute or subchronicpain may be due to surgically correctible pathology (i.e.,adhesions, endometriosis, etc.), once pain has becomechronic (e.g., 6 months), changes in the spinal cord anddorsal root ganglia63–65result in the transmission ofunsolicited, inappropriate, and uncontrolled impulsesto the pain centers of the brain. Pain itself becomesthe disease state rather than a local cause. Although paincan be temporarily arrested by the removal of triggerssuch as endometriosis and adhesions,pain may inevitablyreturn because the neural changes themselves have notbeen addressed, akin to the phenomenon of phantomlimb pain.66Indeed, phantom bladder pain has beenreported in patients after cystectomy.67,68But the story continues. The complex neuroanat-omy of sacral, lumbar, hypogastric, and pelvic plexi69,70affords many opportunities for cross-talk between thenerves of abdominal and pelvic tissues.71Impulses onceappropriate from one organ may trigger impulses in anearby pathway, deceiving the brain into believing thatthey have originated elsewhere. Further, pathology inone organ (e.g., uterus, bladder, bowel) may inducepathology72or hypersensitivity73–75in another. Thus, apatient in whom only one organ was affected initiallymay develop a problem in another.Many studies attest to the coprevalence betweenvarious abdominal and pelvic disorders76,77includingadhesions.78A similar pattern of organ involvementappears to exist from our preliminary analysis of687 female ARD patients from the United Statesresponding to our Internet-based survey (Table 2).Focusing on adhesions and calculating the cumulativecoprevalence of the five most frequent diagnoses orTable 2Women Visiting an Adhesions-Oriented Web SiteConditions and Diagnoses Reported by U.S.Condition or DiagnosisNPercent ofTotal (%)All U.S. women687100Adhesions: abdominal53277Adhesions: pelvic43363Adhesions: abdominal or pelvic58285Chronic abdominal (not pelvic) pain38356Chronic pelvic (not abdominal) pain38356Chronic pain: abdominal or pelvic471 69Irritable bowel syndrome37655Recurrent bowel obstruction29944Endometriosis27040Interstitial cystitis19729Fibroids18327Pelvic Inflammatory Disease (PID) 9814Hemochromatosis or iron overload disorder477Previous hysterectomy 38756DISORDERS OF ADHESIONS OR ARD/WISEMAN361

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conditions, in descending order of prevalence (Table 3),the data reveal a high degree of overlap betweenabdominal or pelvic adhesions, chronic abdominal orpelvic pain, irritable bowel syndrome (IBS), recurrentbowel obstruction, endometriosis, and interstitial cystitis.These data suggest that the severe ‘‘ARD’’ patientsuffers from a similar multifaceted, multiorgan phenom-enon as the ‘‘chronic pelvic’’ or the ‘‘chronic bladder’’ painpatient. Even ifpatients from each of these groups startedwith just one condition, as each condition progressed, itbegan to overlap and coalesced with the other into theentity we have termed CAPPS. Although ?15 millionwomen alone suffer from chronic pelvic pain, we haveconservatively estimated that there are 150,000 to250,000 women with the most severe form of the disease(as CAPPS), a high proportion of who will most likelyhave adhesions.Without the perspective of CAPPS, a patient is atthe mercy of compartmentalized medical practice.Although the severe CPP/IC/ARD patient is likely todisplay several seemingly unrelated symptoms, the mostdominant one will determine the specialty to which thepatient is initially referred. Unexplained dysmenorrhea ordyspareunia will no doubt receive a gynecologic diagnosisof adhesions, pelvic inflammatory disease (PID), orendometriosis. Unexplained bowel disturbances willbe given a diagnosis of IBS from a gastroenterologist,and mysterious voiding issues will be given a diagnosisof IC by a urologist. A neurologist may well view theproblem as one of pudendal neuralgia. Once locked intoa diagnostic paradigm, the patient will be treatedaccordingly and usually in terms of end-organ ratherthan systematic pathology.TREATING THE CAPPS PATIENTGiven the multifaceted nature of CAPPS, it seemsappropriate that the patient be approached by an inte-grated multidisciplinary team including representativesfrom surgery, pharmacy, nursing, pain medicine, nutri-tion, psychology, physiotherapy, neurology, gastroenter-ology, gynecology, urogynecology, urology, psychiatry,and social work.Such a ‘‘biopsychosocial’’ approach79hasbeen introduced, advocated, and to some degree vali-dated in a number of areas of pain medicine, includingpelvic pain.80–86In adopting a multidisciplinary approach, it isessential to avoid the constraints imposed by the para-digms of any one element of the multifaceted condition(e.g., pain, adhesions). Accordingly, the term CAPPS ispreferred over ARD as well as other superficially similarterms such as ‘‘chronic visceral pain syndrome.’’80Per-haps this is what was meant by the recently expressedview that the ‘‘multidisciplinary approach dealing with thepain is far more important than finding an organic causeand cure for the pain.’’81Although for the treatment of aTable 3Coprevalence of Conditions and Diagnoses Reported by U.S. Women Visiting adhesions.org Relative to AdhesionsnPercent(%)nPercent(%)nPercent(%)nPercent(%)nPercent(%)nPercent(%)Total (N¼687)100Adhesions: abdominalor pelvic58285AdhesionsþChronic pain (CP):abdominal or pelvic4716945266AdhesionsþCPþIBS376553605231446AdhesionsþCPþIBSþRecurrent bowelobstruction29944287422373518627AdhesionsþCPþIBSþRecurrentþEndometriosis2703926138228331782611216AdhesionsþCPþIBSþRecurrentþEndometriosisþIC197291932817425149229614659.5% is percentage of total number of U.S. women responding to survey.362SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 26, NUMBER 42008

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patient who has entered the world of CAPPS, it maymatter little that they entered through the door of IC,IBS, endometriosis, or ARD, a new opportunity exists tolearn from CAPPS patients by:1. Adapting therapies used in one variant of CAPPS inpatients with a different variant. For example, sacralnerve stimulation has been shown to be effective intreating IC and is also useful in treating otherCAPPS components such as chronic pelvic pain.87,882. Learning how to prevent patients suffering from the‘‘monolithic’’ varieties of individual diseases fromprogressing to the multifactorial condition.IDENTIFYING RISK FACTORSFOR PROGRESSION TO CAPPSFROM THE PERSPECTIVE OF ARDGenetic FactorsThere has long been speculation about genetic factors inARD. The relative inability to lyse fibrin may predisposea patient to adhesions. Hypofibrinolysis, associated withan allele of the plasminogen activator inhibitor-1 (PAI-1) gene, was found more often in women with endome-triosis than in controls.89More directly related to adhe-sions, carriers of the IL-1RN*2 allele are at greater riskfor adhesion formation.90Multiple SurgeriesA primary occurrence of adhesive small bowel obstruc-tion (ASBO) is itself a risk factor for future obstruction.The rate of recurrence after a first ASBO was calcu-lated91as 16% after 41 months (range, 1 to 75 months),18% at 10 years, and 29% at 30 years.92The risk ofrecurrent ASBO increased with increasing number ofprior SBO episodes and reached 81% for patients with 4or more admissions due to ASBO. Age <40 years, typeof adhesion, and presence of postoperative complicationswere also identified as risk factors for ASBO.91Theeffect of multiple surgeries has been noted in otherCAPPS-related areas. Women with IC had significantlymore pelvic surgeries than did controls, often performedbefore IC was diagnosed and possibly for pain related toundiagnosed IC.93One overlooked consequence ofmultiple surgery is the accumulation of scar tissue withinperitoneal tissue (as opposed to between peritonealtissue, i.e., adhesions) and the effect this may have inentrapping sensory nerves, giving rise to pain and relatedsequelae. Perhaps one effect of repeated surgeries is toincrease the population of fibroblasts of the ‘‘adhesionphenotype,’’94making the recurrence of adhesions evermore likely.HysterectomyHysterectomy is associated with several CAPPS-relatedconditions.95Women with IC (N¼215) had a higher(42%) prevalence of hysterectomies than did controls(21%).93A diagnosis of IC was made 1 to 5 years afterhysterectomy in most of the 68% of the possible cases.93Hysterectomy is also associated with a high rate ofSBO.96Sixty-seven percent of patients admitted forSBO had had a hysterectomy.97The rate of adhesion-related obstruction after gynecologic surgery for benignconditions without hysterectomy has been estimated at?0.3%. With hysterectomy, this rate may be 2 to 3% andwith radical hysterectomy as high as 5%.98Some 56% of our own sample of 687 U.S. womenhad had hysterectomies (Table 2), much higher93,99(p<0.01) than the reported frequencies of 21 toTable 4Overload DisorderFraction of Patients Reporting Various Conditions with or without Hysterectomy or Hemochromatosis/Iron-þHyst387?Hyst300þHyst/?HystþH-I47?H-I640þH-I/?H-INConditionþAdhesions: abdominal or pelvicþChronic pelvic or abdominal painþEndometriosisþInterstitial cystitisþIBSþRecurrent obstructionþFibroidsþPIDþHemochromatosis/ iron-overload disorderHysterectomy0.970.691.401.000.841.200.840.481.760.980.661.470.530.21 2.550.850.362.370.410.123.350.830.253.360.710.34 2.080.980.52 1.900.550.291.860.890.402.230.380.123.280.870.223.930.220.045.070.810.098.620.110.0138.330.910.541.70Geometric mean of fractions/ratios0.440.162.820.900.362.47Hyst, hysterectomy; H-I, hemochromatosis or iron-overload disorder.DISORDERS OF ADHESIONS OR ARD/WISEMAN363

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33%100in control populations. The rates of the variousCAPPS-related conditions in this population was higher(p<0.001) for each of the conditions in patients with ahysterectomy than in those without (Table 4).Whether this effect of hysterectomy is reflectiveof collaterally damaged pelvic structures or a commonpathology predisposing a patient to CAPPS is unclear.Alternatively, hysterectomy may place a woman at riskfor oxidative stress related to iron overload as iron is nolonger eliminated through menstruation.101,102The pro-tective estrogenic effect against oxidative stress may alsohave been a factor.103,104Oxidative stress and its ameli-oration has been discussed in the context of adhe-sions105,106or endometriosis107but not in regard tohysterectomy and adhesions.Susceptibility to Oxidative Stress:Hemochromatosis and Iron-Overload DisorderThe frequency of a diagnosis of hemochromatosis oriron-overload disorder in patients with a hysterectomywas more than 8 times that in patients without(Table 4). The most common form in the UnitedStates is hereditary hemochromatosis (HHC), a reces-sive disorder resulting mainly from one of several HFEgene mutations. HHC affects ?0.5% of the popula-tion108and is characterized by iron deposition inmultiple organs, liver disease, heart disease, joint dis-ease, diabetes, and early death. Its symptoms includefatigue and joint and abdominal pain.109HHC may bea cause of infertility.110Accumulated iron participatesin redox reactions and the generation of reactive oxy-gen species leading to tissue damage via the peroxida-tion of lipids, proteins, and nucleic acid.111,112A rolefor iron has been suggested in the pathogenesis ofendometriosis.113–115Of our sample of U.S. CAPPS-ARD patients,6.8% (47 of 687) reported a diagnosis of hemochroma-tosis (HC) (5.1%) or iron-overload disorder (IOD)(5.7%) with substantial overlap. The frequency of HCpatients is well above that expected (0.5%) in the generalpopulation (p<0.001). The rates of various CAPPS-related conditions in this population was higher(p<0.001) for each of the conditions in patients withHC/IOD than in those without (Table 4).HHC heterozygotes, though not displaying ahistory of HHC, carry risks of iron overload116–119andan altered pattern of fibrosis or inflammation.120,121Because inflammation alters iron homeostasis,122,123HHC heterozygotes (?25% in the United States)undergoing surgery may be at increased risk of adhesionsor other complications and may suffer from more severeforms of other CAPPS-related conditions and may beless responsive to prophylaxis or treatment.Support for this hypothesis comes from ourpreliminary work concerning possible Intergel Reac-tion Syndrome (pIRS).124Intergel (ferric hyaluronate[FeHA]) was a gel of ferric hyaluronate used for adhe-sion prevention but withdrawn due to reports of late-onset pain, unexplained fever, infection, peritoneal re-actions, and several deaths.8,125Based on the possibilitythat the difference between the production of a gran-ulomatous peritonitis in immature and mature rats inresponse to Intergel126could be accounted for by devel-opmental differences in the expression of hepcidin, aregulator of iron transport,127we hypothesized that asimilar subclinical deficiency in iron regulation, such asHHC heterozygosity, may contribute to pIRS. Com-pared with ?25% of the population, 3 of 7 (43%)patients reporting a reaction to Intergel had one of thethree HFE main mutations. These patients, along withtwo others, were of Irish/Scottish ancestry, known tohave a high prevalence of HHC. Three of the HFE-normozygotes and one of the HFE heterozygotes hadhad a prior hysterectomy, a finding that approached(p¼0.08) or exceeded (p¼0.03) significance dependingwhether a figure of 33%100or 21%93,99is taken as thecontrol prevalence of hysterectomy. Thus, the combina-tion of surgery (disturbing iron homeostasis), the pro-pensity to iron overload (either because of a HFEmutation or prior hysterectomy), and the administrationof a bolus dose of iron into a single physiologic compart-ment (as Intergel, delivered intraperitoneally) may haveled to the development of pIRS.This finding has implications beyond pIRS. Be-cause the differences in population frequencies of HFEmutations may account for intercontinental differences inadverse event rates to Intergel,128those same differencesmay influence the relative propensity of populations toform adhesions, to respond to antiadhesion measures,to succumb to other conditions, and for those conditionsto progress to a multifaceted condition such as CAPPS.Otherexamplesofgenesthatregulateoxidationforwhichthis argument could be advanced include those for cat-echol-O-methyltransferase (COMT)129and GTP cyclo-hydrolase (GCH1),130polymorphisms that influencesensitivitytopain.Lastly,thesefindingshaveimplicationsfor the use of antioxidants and modulators of iron metab-olismintheprophylaxisandtreatmentofCAPPS-relatedconditions.CONCLUSIONSAlthough great strides have been made in understandingadhesions, preventing them, and curbing adhesion-re-lated sequelae, ‘‘adhesions’’ can no longer be considered amonolithic entity. Although ‘‘adhesions’’ may start out asa monolithic entity, a patient with ‘‘adhesions’’ maydevelop related conditions (ARD) until they are practi-cally indistinguishable from patients with multiplesymptoms stemming from other pelvic or abdominalpathologies to the point that they coalesce into a new364SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 26, NUMBER 42008